Cardio-cerebrovascular diseases cause great harm to human health, and the resulting morbidity and disability is very high. With the aging population and the decline in the age of onset, the problem is more and more serious. At present, the treatment methods of ischemic heart/cerebral blood vessels mainly include drugs, angioplasty and artery bypass grafting. Current randomized control trial (RCT) research shows that positive drug treatment can achieve the same or even better results than the interventional angioplasty treatment (Lampropoulos C E, Papaioannou I, D'Cruz D P. Osteoporosis—a risk factor for cardiovascular disease? Nature reviews Rheumatology. 2012; 8:587-98). This has led us to reflect on the interventional therapy and the exploration of the treatment of revascularization.
Peripheral arterial disease (PAD) is caused by occlusive atherosclerosis in a vascular bed other than the heart. PAD is now known to be an important public health problem with a total prevalence that is nearly equal to that of coronary artery disease (CAD). The prevalence of PAD increases with age, affecting 6% of individuals aged 50-60 years, and 10-20% of individuals aged >70 years. Despite improvements in medical care and revascularization, patients with critical limb ischaemia continue to have a high risk of major amputation (below the knee or higher) and cardiovascular death. The primary goal of therapy in critical limb ischaemia is to achieve blood flow to the distal limb vessels with angioplasty or bypass surgery. However, many patients with critical limb ischaemia are unsuitable for revascularization, the vessels of patients with extensive occlusion cannot be operated at all, and the long-term re-occlusion rate is high.
Bone marrow derived endothelial progenitor cells (Endothelial Progenitor Cells, EPCs) play important roles in angiogenesis and endothelial homeostasis. Therapeutic angiogenesis, also known as “drug bypass”, uses exogenous vascular growth factor and bone marrow derived EPCs, to promote angiogenesis in ischemic tissue (Therapeutic angiogenesis for critical limb ischaemia. Nature Reviews Cardiology. 2013; 10:387-3967). However, the limitation of therapeutic angiogenesis is that the number of circulating EPCs is low, and aging, diabetes, hyperlipidaemia and other diseases cause the number of circulating EPCs to be even lower (Yao L, et al. Bone marrow endothelial progenitors augment atherosclerotic plaque regression in a mouse model of plasma lipid lowering. Stem Cells. 2012; 30:2720-2731) (Adler B J, et al. Obesity-driven disruption of haematopoiesis and the bone marrow niche. Nature Reviews Endocrinology. 2014; 10:737-748). It is an important therapeutic strategy to increase the number of peripheral blood EPCs by promoting endogenous EPCs mobilization (Liu Y, et al. Beneficial effects of statins on endothelial progenitor cells. Am J Med Sci. 2012; 344:220-226).
It has been traditionally considered that the skeleton is an inert organ that acts as the storage of calcium and phosphorus, protecting the internal organs. Recent studies have found that bone is an important endocrine organ, which is regarded as paradigm of integrative physiology, not only acts as a target organ, but also acts as an important organ to modulate system functions (Karsenty G, Ferron M. The contribution of bone to whole-organism physiology. Nature. 2012; 481:314-320.) (Karsenty G, Oury F. Biology without walls: the novel endocrinology of bone. Annu Rev Physiol. 2012; 74:87-105). It can also regulate the peripheral vasculature by bone-vascular axis (Thompson B, Towler D A. Arterial calcification and bone physiology: role of the bone—vascular axis. Nature Reviews Endocrinology. 2012; 8:529-543). Bone not only contains osteoblasts, osteoclasts and bone cells, but is also rich in endothelial cells, macrophages, nerves and adipose tissue, and even more enriched in a large number of hematopoietic stem cells and bone marrow stromal stem cells. There are two kinds of hematopoietic stem cell niche, the osteoblast niche and endothelial niche, that cooperatively regulate haematopoiesis stem cell proliferation, mobilization and differentiation (Bianco P. Bone and the hematopoietic niche: a tale of two stem cells. Blood. 2011; 117:5281-5288) (Morrison S J, Scadden D T. The bone marrow niche for haematopoietic stem cells. Nature. 2014; 505:327-334).
In recent years, the pleiotropic effects of statins have attracted more and more attention. However, as inhibitors of the rate limiting enzyme of cholesterol synthesis in the liver, less than 5% of statins reached the circulation after oral administration, and even less reached the bone. We have found that intraosseous injection of statins could promote the secretion of insulin and enhance insulin sensitivity, and increase bone mass, improve bone mineral density and improve bone tissue micro structure, and enhance the mechanical properties of bone (CN201210596032.3, CN201210512630.8).
However, it has not previously been reported that intraosseous application of statins can mobilize endogenous endothelial progenitor cells and promote peripheral angiogenesis.